Flexible Roles for Proteoglycan Sulfation and Receptor Signaling

摘要

Proteoglycans (PGs) in the extracellular matrix (ECM) play vital roles in axon growth and navigation, plasticity, and regeneration of injured neurons. Different classes of PGs may support or inhibit cell growth, and their functions are determined in part by highly specific structural features. Among these, the pattern of sulfation on the PG sugar chains is a paramount determinant of a diverse and flexible set of outcomes. Recent studies of PG sulfation illustrate the challenges of attributing biological actions to specific sulfation patterns, and suggest ways in which highly similar molecules may exert opposing effects on neurons. The receptors for PGs, which have yet to be fully characterized, display a similarly nuanced spectrum of effects. Different classes of PG function via overlapping families of receptors and signaling pathways. This enables them to control axon growth and guidance with remarkable specificity, but it poses challenges for determining the precise binding interactions and downstream effects of different PGs and their assorted sulfated epitopes. This review examines existing and emerging evidence for the roles of PG sulfation and receptor interactions in determining how these complex molecules influence neuronal development, growth, and function. Trends Sulfation dictates the actions of PGs. Extensive evidence implies that small modifications in the sulfation pattern lead to significant alterations in function. Chondroitin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPGs) share multiple binding partners and activate overlapping signaling pathways, but often produce different outcomes, with CSPGs generally inhibiting neurite growth and HSPGs supporting it. PG actions may be direct, by interacting with receptors, or indirect, by serving as coreceptors for growth factors and cytokines. Discrete patterning of PGs in the ECM may provide a mechanism by which growth cones respond differently to the same molecular guidance cue. This suggests a pivotal role for PGs in axon navigation that takes advantage of their overlapping signaling pathways and receptor interactions.